Abstract Bacteriophages are viruses that specifically and solely infect bacteria and are a natural platform delivery system of genetic information, encoded by nucleic acids, to bacteria. Lytic bacteriophages do not integrate their DNA into the bacterial chromosome, but replicate independently and ultimately kill their host bacteria. In the early 1900's bacteriophages were used to fight infections in humans, but largely fell to the wayside after the discovery of antibiotics in the 1920's. Only in Eastern Europe and the former Soviet Republics are bacteriophages still considered as effective therapeutic agents. With the antibiotic armamentarium currently challenged by the combination of increasing antibiotic resistance and a dearth of new investment and discovery in new classes of antibiotics, natural bacteriophage therapy is experiencing a renaissance. Along with this renaissance in bacteriophage therapy, advances in systems and synthetic biology now enable exquisite engineering of bacteriophage genomes to introduce nucleic acid therapeutics to alter the physiology, pathogenicity, virulence and antibiotic sensitivity of targeted bacterial species. Bacteriophage can thus be designed to deliver genetic payloads to achieve specific desired effects, such as enhancing antibiotic killing by genetic repression of DNA repair mechanisms, the self-generation of antimicrobial peptides and proteins and expression of enzymes to degrade bacterial biofilms. Biofilm-associated infections are particularly difficult to treat due to the physical and physiological barriers biofilms pose to antimicrobial agents and host defenses. Biofilms are central to the pathogenesis of many serious clinical infections, and often colonize foreign-body surfaces, such as in prosthetic joint infections (PJI). The annual cost of PJI to US hospitals in 2009 was $566M and is projected to increase to $1.62B by 2020. Much of this cost is for surgical replacement of infected prostheses due to the failure of medical treatment. Failure of medical treatment is most problematic in device infections caused by S. aureus, due to its virulence and rapid biofilm formation. This proposal seeks to improve medical treatment for PJI, caused by S. aureus, by utilizing engineered bacteriophage to deliver nucleic acid therapeutics to the bacteria encoding biofilm-degrading enzymes to disperse the protective biofilm. Removal of the biofilm will reduce the inherent tolerance of bacteria to antimicrobial therapy, improve medical treatment outcomes and thereby reduce surgical intervention, prosthesis replacement and the associated health costs and patient burden.